For the past 25 years this grant has investigated health-related consequences associated with marijuana (MJ) smoking and exposure to delta9-tetrahydrocannabinol (THC). We have carried this out with a unique combination of human studies, in vitro experiments, and animal models. In this competing renewal we focus on the role of cannabinoids as immunoregulatory molecules and the mechanisms by which THC suppresses host immunity and increases susceptibility to HIV infection. We have demonstrated that peripheral blood mononuclear cells (PBMC) express cannabinoid receptors and that receptor expression is modulated in MJ smokers, consistent with a direct effect of inhaled THC on circulating immune cells. In modeling the effects of THC on PBMC in vitro, we discovered that THC suppresses human T cell activation and skews cytokine production toward an immunosuppressive profile. Our preliminary studies suggest that both the initiation and maintenance of antigen-specific immunity is impaired by THC. Even more striking, when human PBMC were engrafted into SCID mice, exposure to THC suppressed their capacity to produce IFN-y, enhanced their susceptibility to HIV infection, and dramatically increased systemic viral load. We hypothesize that similar immune modulation occurs in habitual MJ users and may impact their ability to respond to viral infections and vaccines. Three specific aims are proposed: 1) to define the mechanisms by which THC promotes HIV infection in vivo in the huPBL-NOD/SCID/IL2r-gamma-null model, 2) to investigate the mechanisms by which THC alters the induction and maintenance of antigen-specific immune responses against HIV and Hepatitis B antigens in vitro and in the huPBL-NOD/SCID/IL2r-gamma-null model, and 3) to examine the impact of habitual MJ smoking on humoral and cellular immunity to Hepatitis B (HBV) vaccination under controlled MJ exposure conditions. By the conclusion of this work we will have defined several mechanisms by which THC interacts with and promotes HIV infection. We will also have gained important insight into the impact of THC on the generation of anti-viral immunity and the mechanisms mediating these effects. Our prospective vaccination study will be the first of its kind to directly examine MJ smoking for its impact on a clinically relevant immune response. These findings will help define the interrelationships between MJ abuse and opportunistic infections and provide insight into the appropriate design/use of future HIV and HBV vaccine strategies. [unreadable] [unreadable] [unreadable]